The present invention relates to microelectrodes and, more particularly, but not exclusively, to microelectrodes useful for medical purposes, such as, but not limited to, monitoring of electrical activity and stimulation of neurons, e.g., in the central nervous system.
A wide variety of mental and physical processes are controlled or influenced by neural activity in particular regions of the brain. For example, various physical or cognitive functions are directed or affected by neural activity within the sensory or motor cortices. Across most individuals, particular areas of the brain appear to have distinct functions. In the majority of people, for example, the areas of the occipital lobes relate to vision; the regions of the left interior frontal lobes relate to language; portions of the cerebral cortex appear to be consistently involved with conscious awareness, memory, and intellect; and particular regions of the cerebral cortex as well as the basal ganglia, the thalamus and the motor cortex cooperatively interact to facilitate motor function control.
A movement disorder is a neurological disturbance that involves one or more muscles or muscle groups. Movement disorders include Parkinson's disease, Huntington's Chorea, progressive supranuclear palsy, Wilson's disease, Tourette's syndrome, epilepsy, and various chronic tremors, tics and dystonias. Different clinically observed movement disorders can be traced to the same or similar areas of the brain. Abnormalities of basal ganglia, for example, are postulated as a causative factor in diverse movement disorders. More specifically, deficiency of the neurotransmitter dopamine as the consequence of degenerative, vascular or inflammatory changes in the basal ganglia is postulated as the reason for development of Parkinson's disease. Clinical symptoms of the Parkinson's disease, such as rhythmical muscular tremors, rigidity of movement, Destination, droopy posture and masklike facies, are known to appear after 50-60% neuronal loss has occurred in the substantia nigra.
Tremors are characterized by abnormal, involuntary movements. An essential tremor is maximal when the body part afflicted (often an arm or hand) is being used, for example when attempts at writing or fine coordinated hand movements are made. A resting tremor is common in Parkinson's disease and in syndromes with Parkinsonian features. A resting tremor is maximal when the extremities are at rest. Often, when a patient attempts fine movement, such as reaching for a cup, the tremor subsides. Dystonias are involuntary movement disorders characterized by continued muscular contractions which can result in twisted contorted postures involving the body or limbs. Causes of dystonia include biochemical abnormalities, degenerative disorders, psychiatric dysfunction, toxins, drugs and central trauma.
There are a wide variety of treatment modalities for neurological disease in general and movement disorders in particular. These include the use of medicaments (e.g., dopaminergic agonists or anticholinergic agents), tissue ablation (e.g., pallidotomy, thalamotomy, subthalamotomy and other radiofrequency lesioning procedures) and tissue transplantation (e.g., animal or human mesencephalic cells).
Another traditional approach for controlling neurological disease is by electrical stimulation of a predetermined neurological region. The use of electrical stimulation for treating neurological disease, including movement disorders, has been widely discussed in the literature. It has been recognized that electrical stimulation holds significant advantages over radiofrequency lesioning, inasmuch as radiofrequency lesioning can only destroy nervous system tissue. In many instances, the preferred effect is to stimulate to increase, decrease or block neuronal activity. Electrical stimulation permits such modulation of the target neural structures and, equally importantly, does not require the destruction of nervous tissue.
A variety of brain-controlled disorders, including movement disorders, have been found treatable via electrical treatment with deep brain stimulation (DBS). Many disabling symptoms of the Parkinson's disease, including tremor, muscular rigidity, dyskinesia, bradykinesia, and loss of postural stability are known to be effectively treated with a DBS electrode, when traditional medical treatment fails. The neurostimulation blocks the symptoms of the disease resulting in increased quality of life for the patient.
Generally DBS involves placement of a permanent DBS electrode through a burr hole drilled in the patient's skull, and then applying appropriate stimulation through the electrode to the physiological target. To date, DBS has been successfully used in the Vin nucleus, the globus pallidus internal segment (GPi), and the subthalamic nucleus (STN). DBS is particularly effective for relieving of tremors, rigidity, bradykinesia, and dyskinesia. The step of electrode placement during the DBS procedure is very critical, and has been the subject of much attention and research. It is recognized that finding the deep brain target and then placing the permanent electrode such that it efficiently stimulates the target is of utmost importance.
A typical DBS system comprises a pulse generator operatively connected to the brain by one or more permanent electrodes implanted within the patient's brain at a precise location, such that the electrode or electrodes are optimally and safely positioned for the desired stimulation. The electrode is placed in the nervous tissue by a stereotaxic operation whereby the electrode tip is placed in the desired target with an accuracy of a few millimeters. To determine the stereotaxic coordinates of the desired target, a stereotaxic frame is fixed onto the patient's head. The frame functions as an external Cartesian coordinate system with X, Y and Z axes. Once the stereotaxic frame is fixed onto the head, an imaging procedure, such as a computerized tomography (CT) scan or a magnetic resonance imaging (MRI) is performed. The resulting CT or MR images display the brain anatomy and the external stereotaxic frame, and the appropriate coordinate set of any brain region is determined.
It is recognized that if the electrode is located as little as 2 mm away from the desired target, ineffective stimulation results due to several reasons: (i) failure to capture control of the group of neurons, (ii) stimulation of non-desirable areas resulting in unpleasant stimulation, or (iii) necessity for higher stimulus intensities to produce the desired effect resulting in reduced battery life of the implantation, or an any combination of these or other reasons. At least for these reasons, targeting the specific neurons of interest requires high precision and allowance for variability among patients.
Typically, the process of implantation of a DBS electrode follows a step-wise progression of (i) initial estimation of target localization based on imaged anatomical landmarks; (ii) intra-operative microanatomical mapping of key features associated with the intended target of interest; (iii) adjustment of the final target of implantation by appropriate shifts in three dimensional space; and (iv) implantation of the DBS electrode with contacts located at the final desired target.
Thus, for each electrode to be implanted, a burr hole is made in the patient's skull under local anesthesia, and a burr-hole ring is affixed to each opening. Subsequently, a microelectrode is introduced through the burr-hole ring. Test stimulation is performed and a neurologist is simultaneously assessing the stimulation effect on the parkinsonian symptoms of the awake patient. Extracellular recordings are performed, and neuronal activity is displayed. This technique is based on the premise that neurons in one nucleus maybe differentiated from neurons in neighboring nuclei by their electro physiological signatures. If no effect is determined, the microelectrode is advanced stepwise towards the target area along a different trajectory. Test stimulation and neurological assessment are performed at each step. Once the level of maximal stimulation effect is determined, the microelectrode is replaced with a permanent macroelectrode which is affixed to the burr-hole rings. The macroelectrode is connected to a pulse generator which is typically implanted subcutaneously in the pectoral region.
Several DBS systems have been developed over the years. To this end see, e.g., U.S. Pat. Nos. 5,515,848, 5,843,093, 6,560,472, 6,799,074, 6,011,996, 6,094,598, 6,760,626, 6,950,709 and 7,010,356; U.S. Patent Applications No. 20020022872, 20020198446, 20050015130, 20050165465, 20050246004, 2005055064, 20060069415, 20060041284, 20060089697; and International Patent Applications, Publication Nos. WO 1999/036122, WO 2002/011703 and WO 2006/034305.
The above systems, however, suffer from many limitations. Traditionally, the microelectrode used during the stepwise targeting is durable for at most a few stimulations. Since for each trajectory several micro-stimulations are needed, the microelectrode has to be replaced several times during the targeting step. It is recognized that the replacement of the micro-electrode results in severe complication of the procedure because the replaced electrode never return to its original coordinate.
Due to the complex structure of the different nuclei, the size of the macroelectrode, and the inability to place the macroelectrode in the exact center of the nuclei, a large volume of the brain is stimulated, leading to the deactivation of large regions outside the target nucleus and only a partial coverage of the target nucleus. It is appreciated that this limitation results in only partial alleviation of the Parkinson symptoms. Moreover, stimulation of neighboring brain areas results in various complications, such as undesired side effects, include tingling sensation (paresthesia), worsening of symptoms, speech problems (dysarthria, dysphasia), dizziness or lightheadedness (disequilibrium), facial and limb muscle weakness or partial paralysis (paresis), involuntary muscle contractions (dystonia, dyskinesia), movement problems or reduced coordination, jolting or shocking sensation and numbness (hypoesthesia).
It was shown that macro-stimulation during DBS results in contradictory responses in different zones of the STN. While the stimulated nucleus shows inhibition and/or decreased activity [Benazzouz et al., 1995, Neurosci Let 189: 77-80; Benazzouz et al., 2000, Neuroscience 99:289-295; Boraud et al., 1996, Neurosci Let 215:17-20; and Dotrovsky et al., 2000, J. Neurophysiol 84: 570-574.], the efferent nuclei of the stimulated nucleus indicate increase in the activity [Anderson et al., (2003, J. Neurophysiol 89:1150-1160; Hashimoto et al., 2003, J Neurosci 23:1916-1923; Maurice et al., 2003, J Neurosci 23: 9929-9936; Windels et al., 2000, Eur J Neurosci 12:4141-4146; and Windels et al., 2003, J Neurosci Res 72: 259-267].
Although numerous attempts have been made to improve the procedure, e.g., by providing a macroelectrode with several leads, the improvement is still far from being satisfactory. This is primarily due to the size of the macroelectrode which it too large for performing accurate specific stimulation.
The main reason for the lack of suitable electrode for accurate specific stimulation is the difficulty in the manufacturing process. The mechanical and electrical properties of a microelectrode depend on the materials of the microelectrode. Unfortunately, the mechanical and electrical properties of the microelectrode are conflicting features because materials which posses good mechanical properties have less than optimal electrical properties and vice versa. For example, tungsten can be used to manufacture a stiff microelectrode, but such microelectrode is known to undergo corrosion. Platinum-iridium, on the other hand, is a noble metal-alloy which tolerates much against corrosion but is not stiff as tungsten. Moreover, the price of noble metals is expensive, especially iridium.
Numerous attempts have been made to manufacture microelectrodes having improved mechanical and electrical properties. To this end see, e.g., U.S. Pat. Nos. 4,927,515, 4,959,130, 5,178,743, 5,256,205, 5,685,961, 6,301,492, 6,186,090, 6,217,716, 6,343,226 and 6,799,074, and U.S. Patent Application Nos. 20050255242 and 20020041158.
The use of rough metals-alloy films with high dielectric constant such as titanium nitride (TiN) coating on different metal substrate has found increasing interest because of its metal-like conductivity and excellent mechanical and chemical properties. In addition, such metals-alloy films can be coated by the use of physical vapor deposition (PVD), chemical vapor deposition (CVD) processes and atomic layer deposition (ALD). However, heretofore these metals-alloys were only used to manufacture thick substrates, because only thick substances posses sufficient mass and heat capacitance to tolerate the high temperature of the PVD process.
There is thus a widely recognized need for, and it would be highly advantageous to have a microelectrode devoid of the above limitations.